Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which 40% of the amines are protonated. Sevelamer is chemically known as poly(allylamine-co-N,N-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride. Sevelamer hydrochloride is hydrophilic and swells, but is insoluble in water. The structure is represented below

Sevelamer hydrochloride binds phosphate in the gastrointestinal tract to facilitate phosphorus excretion in feces, thereby inhibiting phosphorus absorption from the gut, and lowering the plasma phosphorus concentration. Patients with end-stage renal disease (ESRD) retain phosphate which lead to development of hyperphosphatemia. Phosphorus control is a primary goal in the care of patients with ESRD. Sevelamer hydrochloride which is a calcium-free, aluminium-free phosphate binder, allows physicians to control serum phosphorus in patients with ESRD who are on hemodialysis, without increasing serum calcium levels or contributing an excess calcium load. Clinical studies have shown that Sevelamer provides sustained reduction in markers of soft-tissue and cardiac calcification, such as serum calcium and phosphorus concentrations and parathyroid hormone and also improves blood lipid profiles. Thus, Sevelamer hydrochloride offers the promise of favourably impacting cardiac calcification and thereby reducing patient morbidity and mortality. Sevelamer hydrochloride taken with meals has been shown to decrease serum phosphorus concentrations in patients with ESRD who are on hemodialysis. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders and removal of phosphate with dialysis. Sevelamer hydrochloride treatment results in lowering of low-density lipoprotein (LDL) and total serum cholesterol levels. Sevelamer hydrochloride is indicated for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis and contraindicated in patients with hypophosphatemia or bowel obstruction (see RENAGEL® sevelamer hydrochloride package insert, made of record in Applicant's Information Disclosure Statement). In hemodialysis patients, Sevelamer hydrochloride decreases the incidence of hypercalcemic episodes relative to patients on calcium treatment.
Sevelamer hydrochloride is marketed by Genzyme Corporation as RENAGEL® sevelamer hydrochloride 400 mg and RENAGEL® sevelamer hydrochloride 800 mg tablets. RENAGEL® sevelamer hydrochloride contains hypromellose, diacetylated monoglyceride, colloidal silicon dioxide, and stearic acid as inactive ingredients.
U.S. Pat. No. 5,496,545 discloses a method of removing phosphate from a patient by ion exchange, which involves oral administration of a therapeutically effective amount of a composition containing at least one phosphate-binding polymer that is non-toxic and stable once ingested. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia. It also discloses spectrophotometric phosphate assay (PA) method to determine phosphate binding capacity (PBC) of crosslinked polyallylamine polymers. The PA value of Sevelamer hydrochloride obtained is 3.1 meq/g. It is also disclosed that it is desirous to have higher PA for better activity.
J. R. Mazzeo et al in J. Pharm. Biomed. Anal. 19 (1999) 911-915 teaches HPLC Ion Chromatography PA method for the determination of PBC (phosphate binding capacity) of Sevelamer hydrochloride. The average PA of three Sevelamer hydrochloride batches reported is 5.8 mmol/g.
Commercially available RENAGEL® sevelamer hydrochloride samples, when tested by the HPLC IC method was found to have PA about 5.3 mmol/g, chloride content of about 4.8 meq/g and degree of crosslinking in the range of 10% to 19%. The marketed product had remarkable consistency in its PBC but lacked consistency in its degree of cross linking.
U.S. Pat. No. 4,605,701 discloses process for preparing a cross-linked monoallylamine polymer. The method involves partially neutralizing polyallylamine hydrochloride followed by addition of epichlorohydrin and homogenization.
Further, the suspension obtained was dispersed into a liquid medium that is immiscible with the aqueous solvent in presence of Silvan S-83. However, the said patent does not deal with the properties and applications of the said polymer in phosphate binding.
WO 2006/097942 discloses biphasic process for crosslinking partly neutralized aqueous Polyallylamine hydrochloride using a crosslinking agent in a hydrocarbon solvent in presence of a dispersing agent to get a crosslinked polymer having a desired particle size range (60-100 mesh). The process is carried out in such a manner that aqueous solution is partly neutralized with alkali, mixed with crosslinking agent and charged to an organic phase containing dispersing agent. Crosslinking is carried out at a higher temperature and at a high speed of 800 to 1200 rpm. The crosslinked polymer is then isolated by filtration, followed by water washing to remove salts, followed by isopropyl alcohol (IPA) washing to remove water from the crosslinked polymer and finally drying in a stationary tray dryer.
U.S. Pat. No. 6,525,113 describes process for preparing crosslinked polyallylamine by mixing polyallylamine, water, a hydroxide or alkoxide and a water miscible organic solvent or co-solvent such as acetonitrile followed by the addition of crosslinking agent.
These processes disclosed in above prior arts have drawbacks which are as follows:                (a) Mixing of epichlorohydrin with aqueous solution of partially neutralised Polyallylamine hydrochloride is potentially a risky operation on a large scale because the crosslinking commences immediately upon mixing, which will eventually lead to gelling and pose problems in adding thus thickened gel to the organic phase on a large scale.        (b) The process is carried out at high speed of 800 to 1200 rpm.        (c) Recovery of water miscible solvents like acetonitrile is difficult thus making the process uneconomical and unsuitable on industrial scale.        (d) Washing with methanol or isopropylalcohol (IPA) generates excess of organic effluent, which increases the cost of goods and overheads.        (e) Methanol or IPA is extremely difficult to remove from the crosslinked polymer. Since Sevelamer hydrochloride is an Active Pharmaceutical Ingredient (API), it has to comply stringent ICH guidelines for Organic Volatile Impurities (OVI). Methanol being class II solvent as per the ICH guidelines is allowed maximum of 2000 ppm (0.2%) limit in API. IPA being class III solvent as per the ICH guidelines is allowed maximum of 5000 ppm (0.5%) limit in API. In the desired crosslinked polymer, IPA content is found much above 5000 ppm. The prescribed ICH limit is very stringent and difficult to achieve.        (f) Drying in stationary tray dryer imparts dark yellow colour to the polymer which remains unchanged even after swelling with water.        (g) The prior art processes are not amenable to large scale manufacture, cannot give the desired quality and are uneconomical. Thus there exists a need to develop an economically viable manufacturing process which is amenable to scale up and gives Sevelamer hydrochloride of superior quality.        
Thus there is a need to develop a process for preparing Sevelamer hydrochloride with desired phosphate binding capacity, which simplifies the manufacturing method, minimizes the need for specialized equipments, brings down the need for wash solvents thereby bringing down the manufacturing costs. The present invention provides an economically viable process for preparation of Sevelamer hydrochloride suitable for industrial scale up.
EP0997148 by Chugai Pharmaceuticals discloses tablets which contains phosphate-binding polymers having an average particle size of 400 microns or less and 90% of particles are less than 500 microns and contains crystalline cellulose and/or hydroxypropylcellulose with low degree substitution. Tablets show a moisture content of 1 to 14%.
W00128527 discloses a tablet core which comprises at least about 95% by weight of an aliphatic amine polymer and a process of producing the tablet by hydrating the aliphatic amine polymer to the desired moisture level; blending the aliphatic amine polymer with the excipients in amounts such that the polymer comprises at least about 95% by weight of the resulting blend; and compressing the blend to form tablet core. Tablet is coated with a water based coating.
W002085378 discloses a composition comprising a stable polyallylamine hydrochloride polymer wherein about 4% to about 12% by weight of the polymer is a chloride anion.
EP1153940 discloses phosphate binding polymer having a true specific gravity of 1.18-1.24 and process for producing phosphate binding polymer tablets.
Prior art discloses various formulations of Sevelamer by methods involving direct compression or dry granulation. However, the prior art further states that tableting of phosphate binding polymer Sevelamer by wet granulation is impossible and is difficult to achieve.
The inventors of the present invention tried out several ways for formulating Sevelamer hydrochloride and have successfully developed formulations by high shear non-aqueous granulation which provides improved cohesiveness of particles, excellent flowability and compression characteristics.